FL118: A potential bladder cancer therapeutic compound targeting H2A.X identified through library screening
Related Experiment Video
Updated: Jun 14, 2025
Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model
Published on: May 29, 2015
Guangrui Fan1, Xiongfei Luo2, Yibo Shi1
1Institute of Urology, Lanzhou University Second Hospital, Urinary System Disease Clinical Medical Research Center of Gansu Province, NO. 82 Cuiying Gate, Lanzhou 730000, Gansu Province, China.
Abstract:
The treatment of bladder cancer is limited by low drug efficacy and drug resistance. Hence, this study aimed to screen and identify potential drug precursors and investigate their mechanism of action. A set of camptothecin derivatives showing high anti-tumor potential was selected from early-stage research or literature and synthesized to construct a compound library. A total of 135 compounds were screened in T24 and J82 cells, revealing that FL118 significantly inhibited the proliferation of GC (gemcitabine + cisplatin)-sensitive/insensitive cells. FL118 exhibited excellent penetration and killing ability in organoids and three GC-insensitive patient-derived xenografts. Chemical proteomic and docking calculations were employed to identify binding proteins, indicating that FL118 can bind into H2A.X and its entwined DNA. The results of Cellular thermal shift assay and surface plasmon resonance (Kd = 3.77E-6) support the above findings. Fluorescence localization revealed widespread binding of FL118 within the cell nucleus. Furthermore, WB showed that FL118 increased cellular DNA damage, resulting in significant cell cycle inhibition. The binding of FL118 to H2A.X hindered the damage repair process, leading to apoptosis. Controllable adverse reactions were observed in mice treated with FL118. In conclusion, FL118 may be a superior anti-bladder cancer compound that acts as a molecular glue binding to both H2A.X and DNA. The resistance mediated by the DNA damage repair to DNA damage caused by GC regimen can be reversed by FL118. This distinct mechanism of FL118 has the potential to complement existing mainstream treatment approaches for bladder cancer.
Insights
FL118, a novel compound, effectively targets bladder cancer by inhibiting cell proliferation and overcoming gemcitabine + cisplatin resistance. It acts as a molecular glue, binding H2A.X and DNA to induce apoptosis and hinder DNA repair.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Bladder cancer treatment faces challenges due to low drug efficacy and resistance.
- Novel therapeutic strategies are needed to improve patient outcomes.
Purpose of the Study:
- To screen and identify potential drug precursors for bladder cancer treatment.
- To investigate the mechanism of action of promising compounds.
Main Methods:
- Synthesized a library of 135 camptothecin derivatives.
- Screened compounds in T24 and J82 bladder cancer cells.
- Utilized chemical proteomics, molecular docking, and cellular assays to determine mechanism of action.
Main Results:
- FL118 demonstrated significant inhibition of bladder cancer cell proliferation, including gemcitabine + cisplatin-resistant cells.
- FL118 showed efficacy in organoids and patient-derived xenografts.
- FL118 binds to H2A.X and DNA, hindering DNA repair and inducing apoptosis.
- FL118 exhibited controllable adverse reactions in preclinical models.
Conclusions:
- FL118 is a potential superior anti-bladder cancer compound with a unique molecular glue mechanism.
- FL118 can reverse chemoresistance by targeting DNA damage repair pathways.
- FL118 offers a promising complementary approach to existing bladder cancer treatments.
